The ability of adoptively transferred T cells to mediate in vivo anti-viral effects is now well-documented, particularly in the setting of chronic viral infections such as Epstein Barr virus and cytomegalovirus infections. The principle that adoptively transferred T lymphocytes have therapeutic promise for HIV infection is also well established. However, reproducibly harnessing this activity for chronic HIV infections to provide therapeutic benefit requires that several technical barriers be solved. Our long range goal is to obviate the need of patients to take daily antiviral medications in patients with HIV infection. Our long objective is to establish the safety of infusions of engineered CD8 and CD4 T cells, and to test for improved antiviral efficacy. In this project we will first test the hypothesis that infusions of lentiviral engineered autologous CD8 T cells that have been converted into CTLs by expressing TCR heterodimers that redirect specificity to HLA A2 presented gag epitopes will lead to sustained engraftment and enhanced antiviral effects. In addition, the ability to control escape mutations of the originally isolated (parental) TCR will be compared to an affinity enhanced TCR in this trial. As a complementary strategy we are currently testing the adoptive transfer of CD4 cells that are engineered for resistance to HIV infection using zinc finger nucleases to genetically edit the CCR5 locus. Based on strong preliminary data the specific aims are to: 1) Complete the pre-clinical testing and regulatory requirements necessary to open the CD8 CTL clinical trial; 2) Conduct and analyze a proof of concept clinical trial to determine the safety and relative antiviral efficacy of converted CTLs expressing either the parental or high affinity Gag SL9 TCR in patients with HIV infection and 3) To conduct a second clinical trial testing combination therapy with CCR5 edited CD4 cells and CD8 CTLs expressing Gag SL9 TCRs in patients with HIV infection. Private sector interactions are established with Adaptimmune Ltd. and Sangamo BioSciences, Inc. Together these studies will provide a comprehensive evaluation of the safety and antiviral efficacy of engineered CD4 and CD8 T cells for HIIV/AIDS, and they will move the field forward by providing critical safety data for this new and exciting approach to control HIV infection.